ABSTRACT: Tardive dyskinesia (TD), a drug-induced movement
disorder, is a serious side effect resulting primarily from the
prolonged use of dopamine-blocking agents. TD is distressing because
this adverse effect is likely to be permanent. Age is a consistent risk
factor for TD, and the disorder occurs more frequently in women. Most
treatments for TD have not proven to be successful, and therefore the
best treatment option is prevention of the disorder. If a drug known to
cause TD is prescribed, the clinician should monitor the patient for
symptoms. Early detection may improve the likelihood of remission.

Tardive dyskinesia (TD) is a drug-induced movement disorder (DIMD)
characterized by the presence of abnormal involuntary movements.1-3
TD was named and classified in the early 1960s, a number of years after
chlorpromazine was marketed in the United States as an antipsychotic
agent.4 Chlorpromazine revolutionized the treatment of schizophrenia.4 Neurologic side effects such as involuntary movements and tics began to be reported.2,3
Initially, these neuromuscular disorders (i.e., movement disorders)
were attributed to the psychiatric disease, rather than to incitement by
a drug. However, based on the prevalence of TD in psychiatric patients,
it was eventually established that these movement disorders were linked
to the use of antipsychotics that block dopamine receptors.3

Causes

These early agents used in the treatment of psychosis were termed first-generation antipsychotics (FGAs), or typical antipsychotics. TD has been reported with all FGAs. When the second-generation antipsychotics (SGAs), or atypical antipsychotics,
were developed, researchers expected lower rates of TD based on the
weaker affinity of these drugs for blocking dopamine receptors.5

While the risk of TD may be lower with SGAs, it still does occur. TD
is listed in all of these agents’ package inserts, although clozapine
has had only rare or unconvincing reports of TD.6-10
Quetiapine also appears to have a lower tendency to cause TD; however,
for both quetiapine and clozapine, data have been conflicting.2,7-9

Antipsychotics are the primary drugs associated with TD, but there
are nonpsychiatric drugs that also block dopamine receptors and are
associated with TD (TABLE 1).2,8,9,11 One of these
agents, metoclopramide, has been on the U.S. market since 1979, and its
use has increased over the past decade. In 2009, the FDA issued a
warning about the risk of TD associated with metoclopramide use. At that
time, more than 2 million patients were taking metoclopramide. Failure
to recognize the importance of the warning became a concern because of
the possibility that nonpsychiatric clinicians prescribing
metoclopramide were less familiar with the side effect than were
psychiatric clinicians, who were aware of the connection between
antipsychotics and TD.12

Incidence

TD develops in approximately 20% of patients on long-term
antipsychotic drugs, although there is some debate over a lower
incidence with SGAs.4,13,14 Prevalence rates are widely
variable, depending upon the study design, participants, duration of use
of previous inciting agents, and diagnostic criteria.4 The
incidence of TD with metoclopramide (a gastrointestinal prokinetic agent
used to treat symptomatic gastroesophageal reflux disease, diabetic
gastroparesis, and nausea and vomiting) has been reported to range from
1% to 10%.15 A more recent review of TD associated with metoclopramide stated that the risk may be closer to less than 1%.3,12

DIMD Classification and Symptoms

The various movement disorders—which can be confusing to patients and
clinicians alike—are classified based on timing and specific
symptomatology. There are two major categories of DIMD: acute
(transient) and chronic (persistent). Acute symptoms occur during the
early phase of drug therapy and are frequently short-lived. Chronic
symptoms commonly arise with prolonged use of the inciting drug. Some
thought leaders believe that permanent movement disorders may arise
after a single dose of a dopamine receptor antagonist, but the general
consensus supports the chronic-use concept.13

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),
developed and published by the American Psychiatric Association,
includes classifications of all currently recognized mental health
disorders. In DSM-5, DIMDs are termed medication-induced movement disorders (MIMDs). The MIMDs listed in DSM-5
include neuroleptic-induced parkinsonism and other medication-induced
parkinsonism; neuroleptic malignant syndrome (NMS); medication-induced
acute dystonia; medication-induced acute akathisia; TD; tardive dystonia
and tardive akathisia; medication-induced postural tremor; and other
medication-induced movement disorders (TABLE 2).16

Medication-induced parkinsonism can be misdiagnosed as Parkinson
disease (PD) because of the similarity of symptoms, including tremor,
bradykinesia, and abnormal gait. Sudden transient freezing, one of the
most distressing symptoms of PD, is not seen in medication-induced
parkinsonism.2 NMS, which can be life-threatening, occurs in 0.01% to 0.02% of patients treated with antipsychotics.16
Symptoms of NMS include altered mental status, hyperthermia, altered
blood pressure, tachycardia, tachypnea, and muscle stiffness.16
Withdrawal of the inciting drug, fluid and electrolyte replacement,
lowering of the body temperature, and management of cardiac and renal
complications are essential.3

Acute dystonia and akathisia can occur very quickly after the drug is
taken. Acute dystonia involves abnormal and prolonged contraction of
the muscles of the eye, head, neck, limbs, or trunk.2,16 In
tardive dystonia, a variant of TD, the abnormal movements are distinct
from those of classic TD. TD more often develops in older women; tardive
dystonia more often manifests in younger patients and has no affinity
for gender.2 TD can occur after brief exposure to a dopamine-blocking agent, but it usually manifests after months or years of therapy.3 Acute akathisia is characterized by a sensation of restlessness, a constant urge to move, and anxiety.16
Tardive akathisia, a subtype of TD, occurs after prolonged use of
dopamine-blocking therapy and is clinically similar to acute akathisia.2

Medication-induced postural tremor is expressed as a fine tremor that
occurs when the patient attempts to maintain a posture. The tremor is
similar to that seen with anxiety and the use of caffeine and other
stimulants.16

TD is a DIMD of particular concern for the clinician, patient, and
family because of the severe and potentially irreversible motor effects.
TD is characterized by persistent, involuntary, rapid, and repetitive
stereotypical movements that involve the oral, buccal, and lingual areas
(tongue, cheeks, lips, and jaw). The patient may experience twisting
and protrusion of the tongue, smacking of the lips, and chewing or
puckering of the mouth. Some involuntary movements, such as the tongue
pushing food out of the mouth, can be particularly problematic.4,13,17,18
Frequently, the continual movement of the tongue causes sores to
develop inside the cheeks. This can lead to considerable difficulty for
patients with dentures.13

TD can cause other facial movements, such as grimacing, eyebrow
raising or furrowing, and eye closing. If the limbs are involved, quick
movements of the fingers or toes occur, and nonrhythmic movements of the
arms and legs also take place. The patient may extend the toes and tap
the foot while sitting.4 The larynx and diaphragm may be involved, although they rarely cause vocal or breathing problems.18 The patient may be unaware of the movements or underrate their magnitude.13
Symptoms are more pronounced when the patient is awake and/or excited,
and they tend to resolve during sleep. At times, it may be possible for
the patient to contain the movements with a strong, concentrated effort.4,19
The major risk factors associated with TD are advanced age, female sex,
mood disorders, organic brain dysfunction, greater total drug exposure,
and early extrapyramidal symptoms (EPS).2,4

Etiology

The exact pathophysiology of DIMDs is unknown, but several mechanisms
of action have been proposed. The chronic blockade of dopamine
receptors by these drugs, leading to an escalation in receptor
sensitivity, is one of the most frequently postulated causes.3,20

Diagnosis

To determine whether a patient’s movement disorder is TD, the
clinician first must exclude other movement disorders, and the diagnosis
is usually validated by a physical examination, along with a
neuropsychiatric and medication history.4,7 Several scales
are available to help the clinician accurately assess TD. The Abnormal
Involuntary Movement Scale (AIMS) is widely used to detect TD and track
its severity over a period of time.21 The AIMS includes 12
items that assess orofacial movements, extremity and truncal dyskinesia,
and global severity from the examiner’s evaluation, along with the
patient’s awareness of the movements. The last section of the AIMS
contains questions on problems with teeth and dentures.

Treatment

The optimal treatment path for TD is to prevent the disorder from occurring.11
Many studies have evaluated treatments for TD, with a few showing
slight or modest improvements for patients. In July 2013, the American
Academy of Neurology (AAN) published evidence-based guidelines for the
treatment of tardive syndromes (TDS), including TD.The panel
defined TDS as including lingual-facial-buccal dyskinesia, as well as
the variant forms. TDS encompasses all types of persistent dyskinesia
caused by dopamine-blocking agents.22

TDS are disorders that meet the following criteria: a history of at
least 3 months of neuroleptic exposure; the presence of at least
moderate abnormal involuntary movements in one or more body areas, or at
least mild movements in two or more body areas; and the absence of
other conditions.

The AAN panel recommended that five questions be addressed to
determine the management of TDS, including TD. The questions are as
follows: 1) Is withdrawal of the dopamine receptor blocker an effective
treatment for TDS? 2) Does switching from typical to atypical
dopamine-blocking agents reduce TDS symptoms? 3) What is the efficacy of
pharmacologic agents in treating TDS? 4) Do patients with TDS benefit
from chemodenervation with botulinum toxin? and 5) Do patients with TDS
benefit from surgical therapy?22

The guidelines state that data are insufficient to support or refute
withdrawal of the agent as treatment; however, from a clinical context,
if TDS is present, it is recommended that the clinician withdraw the
antipsychotic. This applies only to patients who can tolerate this,
however. Although evidence is limited, the guidelines note that
short-term withdrawal may worsen TDS, whereas adding an antipsychotic
with stronger EPS can reduce it. Data were insufficient to support or
refute switching from a typical dopamine receptor blocking antagonist to
an atypical agent to reduce TDS symptoms.22

The AAN panel reviewed studies involving several pharmacologic agents
for the treatment of TDS. In a randomized, controlled study, amantadine
(300 mg/day) used conjointly with neuroleptics reduced TDS during the
first 7 weeks. The panel suggested consideration of treatment with
amantadine plus neuroleptics for short-term use, based on weak evidence.22

Tetrabenazine, a dopamine-depleting agent, is licensed in other
countries for treatment of TD. In the U.S., tetrabenazine (Xenazine) is
approved to treat chorea associated with Huntington disease (HD), but
not to treat TD. The initial dosing for HD-associated chorea is 12.5
mg/day.20 The AAN panel found weak evidence to support the
use of tetrabenazine for TDS. In a trial involving haloperidol,
tetrabenazine was dosed at 100 mg/day for 14 weeks. A second
nonrandomized study had participants discontinue the neuroleptic and
other TDS treatments at least 30 days before baseline. Reductions in
symptoms were seen posttreatment with tetrabenazine at a mean dose of
57.9 mg/day.22

Benzodiazepine trials have yielded limited results. In a Cochrane
Review, one small study provided preliminary evidence that
benzodiazepines may have an effect in the treatment of TD.23 Clonazepam
was the benzodiazepine used in this study, and the AAN stated that this
drug may be helpful for short-term (3 months) use in decreasing TD
symptoms, with moderate evidence supporting its use.22

Trials utilizing melatonin, ginkgo biloba, vitamin E, and vitamin B6 have had mixed results.22,24
Melatonin dosed at 2 mg/day was “possibly ineffective,” but a dosage of
10 mg/day for a longer period of time was purported to be feasibly
effective in treating TDS, although the AAN panel deemed that the
evidence was insufficient. There was moderate evidence supporting the
use of ginkgo biloba in inpatients with schizophrenia who had TD.
Vitamin E, which was used to neutralize free radicals,generated
some improvement in newly diagnosed TD present for less than 5 years.
Another study, which used vitamin E dosages of 1,200-1,600 IU/day for 4
to 12 weeks, reported reduced TD severity.22,25 However, the AAN panel determined that the data were conflicting and insufficient to determine efficacy.

Surgical interventions have been explored as treatment for TD. Deep
brain stimulation (DBS), currently used in many PD patients, may be a
potential treatment option for TD.26 A systematic review of
studies (many of which were case studies) in which DBS was used to treat
medication-induced TD and/or dystonia found improvement in these
treatment-resistant patients. Results were not reported for TD and
dystonia separately, although the authors stated that this was not an
issue since most patients experience both conditions. The mean
improvement 3 to 76 months after DBS was 77.5% according to the
Burke-Fahn-Marsden Dystonia Rating Scale.27 However, the AAN deemed that the evidence was insufficient to determine benefit.22

Conclusion

TD can significantly alter the patient’s quality of life. The
pharmacist can actively educate patients about the risk of DIMDs when
the prescribed medications are associated with these side effects. The
pharmacist can also provide patients with information about the initial
signs and symptoms of TD. Remission rates are inversely correlated with
the severity and length of time of TD.17 Early detection may improve the chances of minimizing the disorder or achieving remission.2,21,25,28

U.S. Pharmacist is a monthly journal dedicated to providing the nation's pharmacists with up-to-date,
authoritative, peer-reviewed clinical articles relevant to contemporary pharmacy practice in a variety of settings,
including community pharmacy, hospitals, managed care systems, ambulatory care clinics, home care organizations,
long-term care facilities, industry and academia. The publication is also useful to pharmacy technicians, students,
other health professionals and individuals interested in health management. Pharmacists licensed in the U.S. can earn
Continuing Education credits through Postgraduate Healthcare Education, LLC, accredited by the Accreditation Council for Pharmacy Education (ACPE)
as a provider of continuing pharmacy education.